Substituted semicarbazides and the use thereof

ABSTRACT

This invention is related to substituted semicarbazides represented by Formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein: R 1  and R 2  are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; R 3 , R 4 , R 5  and R 6  are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R 3  and R 4  is defined as above, and R 5  and R 6  together with the nitrogen atom to which they are attached form a heterocycle, including piperidine, piperazine, morpholine; A 1  and A 2  are independently aryl, heteroaryl, saturated or partially unsaturated carbocycle or saturated or partially unsaturated heterocycle, any of which is optionally substituted; X is one of O, S, NR 7 , CH 2 , C(O), NR 7 C(O), C(O)NR 7 , SO, SO 2  or a covalent bond; where R 7  is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; n is 0, 1, 2 or 3. m is 0, 1, 2 or 3. The invention also is directed to the use of substituted semi-carbazides for the treatment of neuronal damage following global and focal ischemia, for the treatment or prevention of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS), and for the treatment, prevention or amelioration of both acute or chronic pain, as anticonvulsants, and as antimanic depressants, as anti-nigraine agents, as local anesthetics, as antiarrhythmics and for the treatment or prevention of diabetic neuropathy.

This application is A 371 of PCT/US 99/02419 filed Feb. 4, 1999.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is in the field of medicinal chemistry. In particular,the invention relates to novel substituted semicarbazides and thediscovery that these compounds are anticonvulsants and act as blockersof sodium (Na⁺) channels.

2. Related Background Art

Several classes of therapeutically useful drugs, including localanesthetics such as lidocaine and bupivacaine, antiarrhythmics such aspropafenone and amioclarone, and anticonvulsants such as lamotrigine,phenytoin and carbamazepine. have been shown to share a common mechanismof action by blocking or modulating Na⁺ channel activity (Catterall, W.A., Trends Pharmacol. Sci. 8:57-65 (1987)). Each of these agents isbelieved to act by interfering with the rapid influx of Na⁺ ions.

Recently, other Na⁺ channel blockers such as BW619C89 and lifarizinehave been shown to be neuroprotective in animal models of global andfocal ischemia and are presently in clinical trials (Graham et al., J.Pharmacol. Exp. Ther. 269:854-859 (1994); Brown et al., British J.Pharmacol. 115:1425-1432 (1995); SCRIP 1870:8 (1993); SCRIP 1773:14(1992)).

The neuroprotective activity of Na⁺ channel blockers is due to theireffectiveness in decreasing extracellular glutamate concentration duringischemia by inhibiting the release of this excitotoxic amino acidneurotransmitter. Studies have shown that unlike glutamate receptorantagonists, Na⁺ channel blockers prevent hypoxic damage to mammalianwhite matter (Stys et al., J. Neurosci. 12:430-439 (1992)). Thus, theymay offer advantages for treating certain types of strokes or neuronaltrauma where damage to white matter tracts is prominent.

Another example of clinical use of a Na⁺ channel blocker is riluzole.This drug has been shown to prolong survival in a subset of patientswith ALS (Bensimm et al., New Engl. J. Med. 330:585-591 (1994)) and hassubsequently been approved by the FDA for the treatment of ALS. Inaddition to the above-mentioned clinical uses, carbamazepine, lidocaineand phenytoin are occasionally used to treat neuropathic pain, such asfrom trigeminal neurologia, diabetic neuropathy and other forms of nervedamage (Taylor and Meldrum, Trends Pharmacol. Sci. 16:309-316 (1995)),and carbamazepine and lamotrigine have been used for the treatment ofmanic depression (Denicott et al., J. Clin. Psychiatry 55: 70-76(1994)).

It has been established that there are at least five to six sites on thevoltage-sensitive Na⁺ channels which bind neurotoxins specifically(Catterall, W. A., Science 242:50-61 (1988)). Studies have furtherrevealed that therapeutic antiarrhythmics, anticonvuisants and localanesthetics whose actions are mediated by Na⁺ channels, exert theiraction by interacting with the intracellular side of the Na⁺ channel andallosterically inhibiting interaction with neurotoxin receptor site 2(Catterall, W. A., Ann. Rev. Pharmacol. Toxicol. 10:15-43 (1980)).

PCT International Published Application WO96/40628 disclosessemicarbazones represented by the following Formula:

where R₁-R₄ are independently hydrogen, halogen, C₁₋₉ alkyl, C₃₋₉cycloalkyl, cyano, C₁₋₉ alkoxy, or C₆₋₁₀ aryloxy; R₅ is hydrogen, C₁₋₉alkyl, C₃₋₉ cycloalkyl, or C₆₋₁₀ aryl; and X is oxygen or sulfur. Thecompounds are disclosed to be useful as anticonvulsants. However, it wasnot suggested or implicated that semicarbazides, which can be preparedby reduction of the semicarbazones, also will act as anticonvulsants.

Dimmock et al., J. Med. Chem. 39:3984-3997 (1996) discloses(aryloxy)aryl semicarbazones that displayed anticonvulsant activitieswhen administered intraperitoneally to mice or orally to rats. However,it was not suggested or implicated that semicarbazides, which can beprepared by reduction of the semicarbazones, also will act asanticonvulsants.

SUMMARY OF THE INVENTION

The present invention is related to the surprising discovery that novelsubstituted semicarbazides represented by Formula I are anticonvulsantsand act as blockers of sodium (Na⁺) channels. Although thesemicarbazides of Formula I can be prepared by reduction of thecorresponding semicarbazones, semicarbazides and semicarbazones are twodifferent classes of compounds. Semicarbazide is a base due to thepresence of the basic N-1 nitrogen. Semicarbazone is not a base but theNH group on N-2 nitrogen is slightly acidic. The C═N double bond insemicarbazone make it a relatively rigid molecule. The C—N single bondin semicarbazide make it a relatively non-rigid molecule. Therefore itis a surprising discovery that semicarbazides of this invention asrepresented by Formula I are anticonvulsants and act as blockers ofsodium (Na⁺) channels, similar to semicarbazones. The invention is alsorelated with treating a disorder responsive to the blockade of sodiumchannels in a mammal suffering from excess activity of said channels byadministering an effective amount of a compound of Formula I asdescribed herein.

The present invention is also directed to the use of a compound ofFormula I for the treatment of neuronal damage following global andfocal ischemia, and for the treatment or prevention of neurodegenerativeconditions such as amyotrophic lateral sclerosis (ALS), as antimanicdepressants, as local anesthetics, as antiarrhythmics, asanticonvulsants and for the treatment or prevention of diabeticneuropathy and for the treatment of pain including both acute andchronic pain and migraine headache.

A first aspect of the present invention is directed to the novelsubstituted semicarbazides of Formula I.

A second aspect of the present invention is directed to the novelcompounds of Formula I as blockers of sodium channels.

A third aspect of the present invention is to provide a method fortreating, preventing or ameliorating neuronal loss following global andfocal ischemia; treating, preventing or ameliorating pain includingacute and chronic pain, and neuropathic pain; treating, preventing orameliorating neurodegenerative conditions; treating, preventing orameliorating manic depression; treating local anesthesia, arrhythmias,and convulsion by administering a compound of Formula I to a mammal inneed of such treatment.

A fourth aspect of the present invention is to provide a pharmaceuticalcomposition useful for treating disorders responsive to the blockade ofsodium ion channels, containing an effective amount of a compound ofFormula I in a mixture with one or more pharmaceutically acceptablecarriers or diluents.

A fifth aspect of the present invention is directed to methods forpreparing novel compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The present invention arises out of the discovery that novel substitutedsemicarbazides of Formula I are anticonvulsants and act as blocker ofthe Na⁺ channel. In view of this discovery, compounds of Formula I areuseful for treating disorders responsive to the blockade of sodium ionchannels.

The compounds useful in this aspect of the present invention are novelsubstituted semicarbazides represented by Formula I:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R₁ and R₂ are independently hydrogen, alkyl, cycloalkyl, alkenyl,alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl orcarboxyalkyl;

R₃, R₄, R₅ and R₆ are independently hydrogen, alkyl, cycloalkyl,alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkylor carboxyalkyl, or R₃ and R₄ is defined as above, and R₅ and R₆together with the nitrogen atom to which they are attached form aheterocycle, including piperidine, piperazine, morpholine;

A₁ and A₂ are independently aryl, heteroaryl, saturated or partiallyunsaturated carbocycle or saturated or partially unsaturatedheterocycle, any of which is optionally substituted;

X is one of O, S, NR₇, CH₂, C(O), NR₇C(O), C(O)NR₇, SO, SO₂ or acovalent bond; where

R₇ is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl,aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl;

n is 0, 1, 2 or 3,

m is 0, 1, 2, or 3.

Preferred compounds falling within the scope of Formula I includecompounds wherein A₁ and A₂ are both aryl moieties, preferably bothphenyl moieties, that are each optionally independently substituted byone to four substituents independently selected from the groupconsisting of halogen, nitro, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, cyano, C₁₋₆ alkoxy or C₆₋₁₀ aryloxy; R₁ and R₂ isindependently hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl or C₆₋₁₀ aryl; R₃,R₄, R₅ and R₆ are independently hydrogen or C₁₋₆ alkyl; X is O; and nand m are 0.

Preferred compounds within Formula I also include those compounds whereA₁ is an optionally substituted aryl group selected from the groupconsisting of phenyl and naphthyl, and A₂ is an optionally substitutedheteroaryl or aryl group selected from the group consisting of pyridyl,pyrimidinyl, 1,3,5-triazinyl, furanyl, thiophenyl, naphthyl, quinolyl,3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl,tetrahydronaphthyl and quinoxalinyl. Also including are biphenylmethyland triphenylmethyl.

Additional preferred compounds within Formula I also include thosecompounds where A₁ is an optionally substituted aryl group selected fromthe group consisting of phenyl or naphthyl, and A₂ is an optionallysubstituted carbocycle or heterocycle selected from the group consistingof cyclopentyl, cyclohexyl, cycloheptyl, piperidinyl, morpholinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclohexenyl,adamantyl, exo-norbornyl and cyclopentenyl.

Additional preferred compounds within Formula I include those compoundswhere A₁ is an optionally substituted heteroaryl or aryl group selectedfrom the group consisting of pyridyl, pyrimidinyl, 1,3,5-triazinyl,naphthyl, quinolyl, furanyl, and thiophenyl, and A₁ is an optionallysubstituted heteroaryl or aryl group selected from the group consistingof phenyl, furanyl, thiophenyl, quinolinyl, 3,4-methylenedioxyphenyl,3,4-ethylenedioxyphenyl, indanyl, tetrahydronaphthyl and naphthyl.

Additional preferred compounds within Formula I include those compoundswhere A₁ is an optionally substituted, saturated or partiallyunsaturated carbocycle or heterocycle selected from the group consistingof cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, piperidinyl,pyrrolidinyl, tetrahydrofuranyl and tetrahydropyranyl, and A₂ is anoptionally substituted aryl or heteroaryl group selected from the groupconsisting of phenyl, furanyl, thiophenyl, quinolinyl,3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl,tetrahydronaphthyl, or naphthyl.

Exemplary preferred compounds that may be employed in this method ofinvention include, without limitation:

1-(4-phenoxybenzyl)semicarbazide;

1-(4-(4-fluorophenoxy)benzyl)semicarbazide;

1-(4-(4-chlorophenoxy)benzyl)semicarbazide;

1-(4-(4-bromophenoxy)benzyl)semicarbazide;

1-(4-(4-methoxyphenoxy)benzyl)semicarbazide;

1-(4-(4-trifluoromethylphenoxy)benzyl)semicarbazide;

1-(4-(4-methylphenoxy)benzyl)semicarbazide;

1-(4-(3,4-difluorophenoxy)benzyl)semicarbazide;

1-(4-(4-chloro-2-fluorophenoxy)benzyl)semicarbazide;

1-(4-(4-nitrophenoxy)benzyl)semicarbazide;

1-(4-(3-methylphenoxy)benzyl)semicarbazide;

1-(4-(4-t-butylphenoxy)benzyl)semicarbazide;

1-(4-(4-propylphenoxy)benzyl)semicarbazide;

1-(4-(4-s-butylphenoxy)benzyl)semicarbazide;

1-(4-(3,4-methylenedioxyphenoxy)benzyl)semicarbazide;

1-(4-cyclohexyloxybenzyl)semicarbazide;

1-(4-cycloheptyloxybenzyl)semicarbazide;

1-(4-(5-indanyloxy)benzyl)semicarbazide;

1-(4-(6-quinolinyloxy)benzyl)semicarbazide;

1-(4-(4-fluorophenoxy)-3-fluorobenzyl)semicarbazide;

1-(4-(tetrahydropyranyloxy)benzyl)semicarbazide;

1-(4-(4-fluorophenoxy)benzyl-4-methylsemicarbazide; and

1-(4-(4-fluorophenoxy)benzyl)-2-methylsemicarbazide.

Since the compounds of Formula I are blockers of sodium (Na⁺) channels,a number of diseases and conditions mediated by sodium ion influx can betreated employing these compounds. Therefore, the invention is relatedto a method of treating, preventing or ameliorating neuronal lossassociated with stroke, global and focal ischemia, CNS trauma,hypoglycemia and surgery, spinal cord trauma; as well as treating orameliorating neurodegenerative diseases including Alzheimer's disease,amyotrophic lateral sclerosis, Parkinson's disease, treating orameliorating anxiety, convulsions, glaucoma, migraine headache, andmuscle spasm. The compounds of Formula I are also useful as antimanicdepressants, as local anesthetics, and as antiarrhythmics; as well asfor treating, preventing or ameliorating pain including surgical,chronic and neuropathic pain. In each instance, the methods of thepresent invention require administering to an animal in need of suchtreatment an effective amount of a sodium channel blocker of the presentinvention, or a pharmaceutically acceptable salt or prodrug thereof.

Specifically, preferred substituted semicarbazides are represented byFormulae II-VI. In particular, a preferred embodiment is represented byFormulae II:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R₁, R₂, R₃, R₄, R₅, R₆, X, n and m are as defined previously withrespect to Formula I; and

R₉, R₁₀, R₁₁ and R₁₂ independently are hydrogen, halo, haloalkyl, aryl,cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl,alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl,heteroarylalkyl, hetroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl,heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl,nitro, amino, ureido, cyano, acylamido, hydroxy, thiol, acyloxy, azido,alkoxy, carboxy, carbonylamido or alkylthiol; or

R₉ and R₁₀ or R₁₁ and R₁₂ are taken together with the carbon atoms towhich they are attached to form a carbocycle or heterocycle. Examples ofbridges formed by R₉ and R₁₀ or R₁₁ and R₁₂ taken together are —OCH₂O—,—OCF₂O—, —CH₂)₃—, —(CH₂)₄—, —OCH₂CH₂O—, —CH₂N(R₁₈)CH₂—,—CH₂CH₂N(R₁₈)CH₂—, —CH₂N(R₁₈)CH₂CH₂— and —CH═CH—CH═CH—; where R₁₈ ishydrogen, alkyl or cycloalkyl;

R₁₃, R₁₄, R₁₅, R₁₆ and R₁₇ independently are hydrogen, halo, haloalkyl,aryl, cycloalkyl, saturated or partially unsaturated heterocycle,heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl,arylalkynyl, heteroarylalkyl, hetroarylalkenyl, heteroarylalkynyl,cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl,carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamido,hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido oralkylthiol; or

one of R₁₃ and R₁₄ or R₁₄ and R₁₅, or R₁₅ and R₁₆, or R₁₆ and R₁₇ aretaken together with the carbon atoms to which they are attached to forma carbocycle or heterocycle. Examples of bridges formed by R₁₃ and R₁₄,or R₁₄ and R₁₅, or R₁₅ and R₁₆, or R₁₆ and R₁₇ taken together are—OCH₂O—, —OCF₂O—, —(CH₂)₃—, —(CH₂)₄—, —OCH₂CH₂O—, —CH₂N(R₁₈)CH₂—,—CH₂CH₂N(R₁₈)CH₂—, —CH₂N(R₁₈)CH₂CH₂— and —CH═CH—CH═CH—; where R₁₈ ishydrogen, alkyl or cycloalkyl.

Another preferred embodiment of the invention includes substitutedsemicarbazides represented by Formula III and Formula IV:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R₁-R₆, R₉-R₁₂, R₁₃-R₁₇, n, m, A₁, A₂ and X are as defined previouslywith respect to Formulae I and II;

Preferred compounds within Formula III include those compounds where A₂is an optionally substituted heteroaryl or aryl group selected from thegroup consisting of pyridyl, pyrimidinyl, 1,3,5-triazinyl, naphthyl,quinolyl, furanyl, and thiophenyl.

Preferred compounds within Formula IV include those compounds where A₁is an optionally substituted heteroaryl or aryl group selected from thegroup consisting of pyridyl, pyrimidinyl, 1,3,5-triazinyl, naphthyl,quinolyl, furanyl, and thiophenyl.

Another preferred embodiment of the invention includes substitutedsemicarbazides represented by Formula V and Formula VI:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R₁-R₆, R₉-R₁₂, R₁₃-R₁₇, n, m and X are as defined previously withrespect to Formulae I and II; and

B₁ is an optionally substituted, saturated or partially unsaturatedcarbocycle or optionally substituted, saturated or partially unsaturatedheterocycle; and

B₂ is an optionally substituted, saturated or partially unsaturatedcarbocycle or optionally substituted, saturated or partially unsaturatedheterocycle.

Preferred B₁ and B₂ independently include cyclopentyl, cyclohexyl,cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl orpiperidinyl.

Generally, preferred compounds of Formulae I-VI are those compoundswhere R₁ and R₂ is hydrogen or alkyl, more preferably hydrogen, methylor ethyl, and where R₃ and R₄ are independently hydrogen or C₁₋₄ alkyl.

Preferred values of X in Formulae I-VI are O.

Preferred values of R₅-R₆ with respect to Formulae I-VI are hydrogen orC₁₋₄ alkyl.

Preferred values of R₉-R₁₂, and R₁₃-R₁₇, with respect to Formulae II-VIinclude hydrogen, halo, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₄-C₇ cycloalkyl,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ aryl(C₁-C₆)alkyl,C₆-C₁₀ aryl(C₂-C₆)alkenyl, C_(6-C) ₁₀ aryl(C₂-C₆)alkynyl, C₁-C₆hydroxyalkyl, nitro, amino, ureido, cyano, C₁-C₆ acylamido, hydroxy,thiol, C₁-C₆ acyloxy, azido, C₁-C₆ alkoxy, or carboxy. Alternatively, R₉and R₁₀ or R₁₁ and R₁₂, or two adjacent R₁₃ through R₁₇ can form abridge selected from the group consisting of —OCH₂O—, —CH₂)₃—, —CH₂)₄—,—OCH₂CH₂O—, —CH₂N(R₁₈)CH₂—, —CH₂CH₂N(R₁₈)CH₂—, —CH₂N(R₁₈)CH₂CH₂—, and—CH═CH—CH═CH—, where R18 is hydrogen or C₁-C₆ alkyl.

With respect to the novel methods of treatment of the present invention,an additional preferred subset of substituted semicarbazides includescompounds of Formula I, wherein A₁ and A₂ are phenyl moieties, that areeach independently substituted by one or two substituents independentlyselected from the group consisting of hydrogen, halogen, C₁₋₆ alkyl,C₃₋₈ cycloalkyl, cyano, C₁₋₆ alkoxy or C₆₋₁₀ aryloxy; R₁ and R₂ ishydrogen, C₁₋₆ alkyl, or C₃₋₈ cycloalkyl; R₃ and R₄ is hydrogen, or C₁₋₆alkyl; X is O; n and mis 0.

Useful compounds in this aspect of the present invention include:

1-(4-phenoxybenzyl)semicarbazide;

1-(4-(4-fluorophenoxy)benzyl)semicarbazide;

1-(4-(4-chlorophenoxy)benzyl)semicarbazide;

1-(4-(4-bromophenoxy)benzyl)semicarbazide;

1-(4-(4-methoxyphenoxy)benzyl)semicarbazide;

1-(4-(4-trifluoromethylphenoxy)benzyl)semicarbazide;

1-(4-(4-methylphenoxy)benzyl)semicarbazide;

1-(4-(3,4-difluorophenoxy)benzyl)semicarbazide;

1-(4-(4-chloro-2-fluorophenoxy)benzyl)semicarbazide;

1-(4-(4-nitrophenoxy)benzyl)semicarbazide;

1-(4-(3-methylphenoxy)benzyl)semicarbazide;

1-(4-(4-t-butylphenoxy)benzyl)semicarbazide;

1-(4-(4-propylphenoxy)benzyl)semicarbazide;

1-(4-(4-s-butylphenoxy)benzyl)semicarbazide;

1-(4-(3,4-methylenedioxyphenoxy)benzyl)semicarbazide;

1-(4-cyclohexyloxybenzyl)semicarbazide;

1-(4-cycloheptyloxybenzyl)semicarbazide;

1-(4-(5-indanyloxy)benzyl)semicarbazide;

1(4-(6-quinolinyloxy)benzyl)semicarbazide;

1-(4-(4-fluorophenoxy)-3-fluorobenzyl)semicarbazide;

1-(4-(tetrahydropyranyloxy)benzyl)semicarbazide;

1-(4-(4-fluorophenoxy)benzyl-4-methylsemicarbazide; and

1-(4-(4-fluorophenoxy)benzyl)-2-methylsemicarbazide.

Useful aryl groups are C₆₋₁₄ aryl, especially C₆₋₁₀ aryl. Typical C₆₋₁₄aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl,azulenyl, biphenyl, biphenylenyl and fluorenyl groups.

Useful cycloalkyl groups are C₃₋₈ cycloalkyl. Typical cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl andcycloheptyl.

Usefull saturated or partially saturated carbocyclic groups arecycloalkyl groups as defined above, cycloalkenyl groups, such ascyclopentenyl, cycloheptenyl and cyclooctenyl, bicycloalkyl groups suchas norbornyl groups, as well as tetrahydronaphthyl and indanyl groups.

Useful halo or halogen groups include fluorine. chlorine, bromine andiodine.

Useful alkyl groups include straight-chained and branched C₁₋₁₀ alkylgroups, more preferably C₁₋₆ alkyl groups. Typical C₁₋₁₀ alkyl groupsinclude methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl,3-pentyl, hexyl and octyl groups. Also contemplated is a trimethylenegroup substituted on two adjoining positions on the benzene ring of thecompounds of the invention.

Useful alkenyl groups are C₂₋₆ alkenyl groups, preferably C₂₋₄ alkenyl.Typical ₂₋₁₄ alkenyl groups include ethenyl, propenyl, isopropenyl,butenyl, and sec.-butenyl.

Useful alkynyl groups are C₂₋₆ alkynyl groups, preferably C₂₋₄ alkynyl.Typical C₂₋₁₄ alkynyl groups include ethynyl, propynyl, butynyl, and2-butynyl groups.

Useful arylalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted by any of the above-mentioned C₆₋₁₄ aryl groups.Usefull values include benzyl, phenethyl and naphthylmethyl.

Useful arylalkenyl groups include any of the above-mentioned C₂₋₄alkenyl groups substituted by any of the above-mentioned C₆₋₁₄ arylgroups.

Useful arylalkynyl groups include any of the above-mentioned C₂₋₄alkynyl groups substituted by any of the above-mentioned C₆₋₁₄ arylgroups. Useful values include phenylethynyl and phenylpropynyl.

Useful cycloalkylalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by any of the above-mentioned cycloalkylgroups.

Useful haloalkyl groups include C₁₋₁₀ alkyl groups substituted by one ormore fluorine, chlorine, bromine or iodine atoms, e.g. fluoromethyl,difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl andtrichloromethyl groups.

Useful hydroxyalkyl groups include C₁₋₁₀ alkyl groups substituted byhydroxy, e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl andhydroxybutyl groups.

Useful alkoxy groups include oxygen substituted by one of the C₁₋₁₀alkyl groups mentioned above.

Useful alkylthio groups include sulphur substituted by one of the C₁₋₁₀alkyl groups mentioned above.

Useful acylamino groups are any C₁₋₆ acyl (alkanoyl) attached to anamino nitrogen, e.g. acetamido, propionamido, butanoylamido,pentanoylamido, hexanoylamido as well as aryl-substituted C₂₋₆substituted acyl groups.

Useful acyloxy groups are any C₁₋₆ acyl (alkanoyl) attached to an oxy(—O—) group, e.g. acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy,hexanoyloxy and the like.

Useful saturated or partially saturated heterocyclic groups includetetrahydrofuranyl, pyranyl, piperidinyl, piperizinyl, pyrrolidinyl,imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl,morpholinyl, isochromanyl, chromanyl, pyrazolidinyl and pyrazolinylgroups.

Useful heterocycloalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by any of the above-mentioned heterocyclicgroups.

Useful heteroaryl groups include any one of the following: thienyl,benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl,isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, 2H-pyrrolyl,pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl,purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl,naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, 5aH-carbazolyl,carbazolyl, β-carbolinyl, phenanthridinyl, acrindinyl, perimidinyl,phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl,furazanyl. phenoxazinyl, 1,4-dihydroquinoxaline-2,3-dione,7-aminoisocoumarin pyrido[1,2-a]pyrimidin-4-one, 1,2-benzoisoxazol-3-yl,4-nitrobenzofurazan, benzimidazolyl, 2-oxindolyl and2-oxobenzimidazolyl. Where the heteroaryl group contains a nitrogen atomin a ring, such nitrogen atom may be in the form of an N-oxide, e.g. apyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide and the like.

Useful heteroarylalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by any of the above-mentioned heteroarylgroups.

Useful heteroarylalkenyl groups include any of the above-mentioned C₂₋₄alkenyl groups substituted by any of the above-mentioned heteroarylgroups.

Useful heteroarylalkynyl groups include any of the above-mentioned C₂₋₄alkynyl groups substituted by any of the above-mentioned heteroarylgroups.

Usefull amino groups include —NH₂, —NHR₁₄, and —NR₁₄R₁₅, wherein R₁₄ andR₁₅ are C₁₋₁₀ alkyl or cycloalkyl groups as defined above.

Useful aminocarbonyl groups are carbonyl groups substituted by —NH₂,—NHR₁₄, and —NR₁₄R₁₅, wherein R₁₄ and R₁₅ are C₁₋₁₀ alkyl groups.

Optional substituents on any of the aryl, heterocyclic, heteroaryl, andcycloalkyl rings in Formulae I-VI include any one of halo, haloalkyl,aryl, heterocycle, cycloalkyl, heteroaryl, alkyl, alkenyl, alkynyl,arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl,heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl,aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano,acylamino, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy,aminocarbonyl, and alkylthiol groups mentioned above. Preferred optionalsubstituents include: halo, haloalkyl, hydroxyalkyl, aminoalkyl, nitro.alkyl alkoxy and amino.

Certain of the compounds of Formula I may exist as optical isomers andthe invention includes both the racemic mixtures of such optical isomersas well as the individual entantiomers that may be separated accordingto methods that are well know to those of ordinary skill in the art.

Examples of pharmaceutically acceptable addition salts include inorganicand organic acid addition salts such as hydrochloride, hydrobromide,phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate,mandelate, acetic acid, dichloroacetic acid and oxalate.

Examples of prodrugs include esters or amides of Formula I with R₁-R₆ ashydroxyalkyl or aminoalkyl, and these may be prepared by reacting suchcompounds with anhydrides such as succinic anhydride.

The invention is also directed to a method for treating disordersresponsive to the blockade of sodium channels in animals sufferingthereof. Particular preferred embodiments of the substitutedsemicarbazides for use in method of this invention are represented bypreviously defined Formula I.

The compounds of this invention may be prepared using methods known tothose skilled in the art, or by the novel methods of this invention.Compounds with Formulae I-VI can be prepared as illustrated by exemplaryreaction in Scheme I from reduction of the corresponding semicarbazones.

The compounds of the present invention were assessed byelectrophysiological assays in dissociated hippocampal neurons forsodium channel blocker activity. These compounds also could be assayedfor binding to the neuronal voltage-dependent sodium channel using ratforebrain membranes and [³H]BTX-B.

Sodium channels are large transmembrane proteins that are expressed invarious tissues. They are voltage sensitive channels and are responsiblefor the rapid increase of Na⁺ permeability in response to depolarizationassociated with the action potential in many excitable cells includingmuscle, nerve and cardiac cells.

One aspect of the present invention is the discovery of the mechanism ofaction of the compounds herein described as specific Na⁺ channelblockers. Based upon the discovery of this mechanism, these compoundsare contemplated to be useful in treating or preventing neuronal lossdue to focal or global ischemia, and in treating or preventingneurodegenerative disorders including ALS, anxiety, and epilepsy. Theyare also expected to be effective in treating, preventing orameliorating neuropathic pain, surgical pain and chronic pain. Thecompounds are also expected to be useful as antiarrhythmics, anestheticsand antimanic depressants.

The present invention is directed to compounds of Formulae I that areblockers of voltage-sensitive sodium channels. According to the presentinvention, those compounds having preferred sodium channel blockingproperties exhibit an IC₅₀ of about 100 μM or less in theelectrophysiological assay described herein. Preferably, the compoundsof the present invention exhibit an IC₅₀ of 10 μM or less. Mostpreferably, the compounds of the present invention exhibit an IC₅₀ ofabout 1.0 μM or less. Substituted semicarbazides of the presentinvention may be tested for their Na⁺ channel blocking activity by thefollowing electrophysiological and binding assays.

Electrophysiological Assay:

Cellpreparation: HEK-293 cells stably expressing the hSkM1 isoform ofNa⁺ channels (generous gift from Dr. A. L. George, Vanderbilt UniversityMedical School) were cultured using standard techniques, as describedpreviously (Verdoorn, T. A, et al., Neuron 4:919-928 (1990)). Forelectrophysiology, cells were plated onto 35 mm Petri dishes (pre-coatedwith poly-D-lysine) at a density of 1:40 on the day of re-seeding fromconfluent cultures. Cells are suitable for recordings for 2-3 days afterplating.

Patch-clamp recordings of voltage-sensitive Na⁺ currents: Whole-cellvoltage-clamp recordings were made using conventional patch-clamptechniques (Hamill et al, Pfluegers Arch. 391:85-100 (1981)) with anAxopatch 200 A amplifier (Axon Instruments, Foster City, Calif.).Recordings were made within 2-3 hours after neuron dissociation. Therecording chamber was continuously superfused with the external solution(150 mM NaCl, 5.4 mM KCl, 1.8 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, 10 mMglucose, pH 7.4 (NaOH)) at a speed of about 1 ml/min. Recording pipetteswere pulled from thick-walled capillaries (WPI, Sarasota, Fla.) andfire-polished. The pipette resistances ranged from 1 to 3 MΩ when thepipettes were filled with internal solution containing (in mM): 110 CsF,10 NaCl, 5 MgCl₂, 11 EGTA, 10 HEPES, pH adjusted to 7.4 with CsOH.Osmolality was set with a difference of 15-20 mmol/kg between externaland internal solutions (lower inside the cell). Drugs and interveningwash-outs were applied through a linear array of flow pipes (DrummondMicrocaps, 2-μl, 64-mm length). Compounds are dissolved indimethylsulfoxide (DMSO) to make a 30 mM stock solution, which wassubsequently diluted into the external solution to give finalconcentrations of 0.1-100 μM. At the highest (1%) concentration, DMSOinhibited the size of Na⁺ current only slightly. Currents were recordedat room temperature (22-25° C.), filtered at 5 kHz with an active 8-poleBessel filter (Frequency Devices, Haverhill, Mass.), digitized at10-50-μs intervals, and stored using Digidata 1200 analog/digitalinterface with Pclamp6/Clampex software (Axon Instruments). Seriesresistance was cancelled typically by ˜75% when necessary. Theinhibitory potency of drugs was assessed by measuring reductions in thepeak amplitude of Na⁺ currents induced by increasing concentrations ofcompounds tested. Na⁺ currents were elicited by stepping membranevoltage from holding potentials over the range −100 mV to −50 mV, to apulse potential of −10 mV. The test pulse duration was 5-10 msec,repeated at a frequency ≦1 Hz. Concentration-inhibition curves werefitted with equation 1:

I/I_(control)=1/(1+([compound]/IC₅₀))  Eq. 1

where I_(control) is the maximal Na⁺ current in the absence ofantagonist, [compound] is the drug concentration, and IC₅₀ is theconcentration of compound that produces half maximal inhibition.

Binding Assay:

The ability of compounds of the present invention to modulate eithersite 1 or site 2 of the Na⁺ channel was determined following theprocedures fully described in Yasushi, J. Biol. Chem. 261:6149-6152(1986) and Creveling, Mol. Pharmacol. 23:350-358 (1983), respectively.Rat forebrain membranes were used as sources of Na⁺ channel proteins.The binding assays were conducted in 130 μM choline chloride at 37° C.for 60-minute incubation with [³H] saxitoxin and [³H] batrachotoxin asradioligands for site 1 and site 2, respectively.

The compounds of the present invention may be tested for in vivoanticonvulsant activity after iv. po or ip injection using a number ofanticonvulsant tests in mice (audiogenic seizure model in DBA-2 mice,pentylenetetrazol-induced seizures in mice, maximum electroshock seizuretest (MES)).

The compounds may be tested for their neuroprotective activity afterfocal and global ischemia produced in rats or gerbils according to theprocedures described in Buchan et al. (Stroke, Suppl. 148-152 (1993))and Sheardown et al. (Eur. J. Pharmacol. 236:347-353 (1993)) and Grahamet al. (J. Pharmacol Exp. Therap. 276:1-4 (1996)).

The compounds may be tested for their neuroprotective activity aftertraumatic spinal cord injury according to the procedures described inWrathall et. al. (Exp. Neurology 137:119-126 (1996)) and Iwasaki et. al.(J. Neuro Sci. 134:21-25 (1995)).

Compositions within the scope of this invention include all compositionswherein the compounds of the present invention are contained in anamount which is effective to achieve its intended purpose. Whileindividual needs vary, determination of optimal ranges of effectiveamounts of each component is within the skill of the art. Typically. thecompounds may be administered to mammals, e.g. humans, orally at a doseof 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceuticallyacceptable salt thereof, per day of the body weight of the mammal beingtreated for epilepsy, neurodegenerative diseases, anesthetic,arrhythmia, manic depression, and pain. For intramuscular injection, thedose is generally about one-half of the oral dose.

In the method of treatment or prevention of neuronal loss in global andfocal ischemia, brain and spinal cord trauma, hypoxia, hypoglycemia,status epilepsy and surgery, the compound can be administrated byintravenous injection at a dose of about 0.025 to about 10 mg/kg.

The unit oral dose may comprise from about 0.01 to about 50 mg,preferably about 0.1 to about 10 mg of the compound. The unit dose maybe administered one or more times daily as one or more tablets eachcontaining from about 0.1 to about 10, conveniently about 0.25 to 50 mgof the compound or its solvates.

In addition to administering the compound as a raw chemical, thecompounds of the invention may be administered as part of apharmaceutical preparation containing suitable pharmaceuticallyacceptable carriers comprising excipients and auxiliaries whichfacilitate processing of the compounds into preparations which can beused pharmaceutically. Preferably, the preparations, particularly thosepreparations which can be administered orally and which can be used forthe preferred type of administration, such as tablets, dragees, andcapsules, and also preparations which can be administered rectally, suchas suppositories, as well as suitable solutions for administration byinjection or orally, contain from about 0.01 to 99 percent, preferablyfrom about 0.25 to 75 percent of active compound(s), together with theexcipient.

Also included within the scope of the present invention are thenon-toxic pharmaceutically acceptable salts of the compounds of thepresent invention. Acid addition salts are formed by mixing a solutionof the particular 2-aminoacetamide of the present invention with asolution of a pharmaceutically acceptable non-toxic acid such ashydrochloric acid, fumaric acid, maleic acid, succinic acid, aceticacid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalicacid, dichloroacetic acid, and the like. Basic salts are formed bymixing a solution of the particular 2-aminoacetamide of the presentinvention with a solution of a pharmaceutically acceptable non-toxicbase such as sodium hydroxide, potassium hydroxide, choline hydroxide,sodium carbonate and the like.

The pharmaceutical compositions of the invention may be administered toany animal which may experience the beneficial effects of the compoundsof the invention. Foremost among such animals are mammals, e.g., humans,although the invention is not intended to be so limited.

The pharmaceutical compositions of the present invention may beadministered by any means that achieve their intended purpose. Forexample, administration may be by parenteral, subcutaneous, intravenous,intramuscular, intraperitoneal, transdermal, or buccal routes.Alternatively, or concurrently, administration may be by the oral route.The dosage administered will be dependent upon the age, health, andweight of the recipient, kind of concurrent treatment, if any, frequencyof treatment, and the nature of the effect desired.

The pharmaceutical preparations of the present invention aremanufactured in a manner which is itself known, for example, by means ofconventional mixing, granulating, dragee-making, dissolving, orlyophilizing processes. Thus, pharmaceutical preparations for oral usecan be obtained by combining the active compounds with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

Suitable excipients are, in particular, fillers such as saccharides, forexample lactose or sucrose, mannitol or sorbitol, cellulose preparationsand/or calcium phosphates. for example tricalcium phosphate or calciumhydrogen phosphate, as well as binders such as starch paste, using, forexample, maize starch, wheat starch, rice starch, potato starch,gelatin, tragacanth, methyl cellulose, hydroxy-propylmethylcellulose,sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,disintegrating agents may be added such as the above-mentioned starchesand also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar,or alginic acid or a salt thereof, such as sodium alginate. Auxiliariesare, above all, flow-regulating agents and lubricants, for example,silica, talc, stearic acid or salts thereof, such as magnesium stearateor calcium stearate, and/or polyethylene glycol. Dragee cores areprovided with suitable coatings which, if desired, are resistant togastric juices. For this purpose, concentrated saccharide solutions maybe used which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquersolutions and suitable organic solvents or solvent mixtures. In order toproduce coatings resistant to gastric juices, solutions of suitablecellulose preparations such as acetylcellulose phthalate orhydroxypropymethyl-cellulose phthalate, are used. Dye stuffs or pigmentsmay be added to the tablets or dragee coatings, for example, foridentification or in order to characterize combinations of activecompound doses.

Other pharmaceutical preparations which can be used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain the active compounds in the form of granules whichmay be mixed with fillers such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds are preferablydissolved or suspended in suitable liquids, such as fatty oils, orliquid paraffin. In addition, stabilizers may be added.

Possible pharmaceutical preparations which can be used rectally include,for example, suppositories, which consist of a combination of one ormore of the active compounds with a suppository base. Suitablesuppository bases are, for example, natural or synthetic triglycerides,or paraffin hydrocarbons. In addition, it is also possible to usegelatin rectal capsules which consist of a combination of the activecompounds with a base. Possible base materials include, for example,liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, for example,water-soluble salts and alkaline solutions. In addition, suspensions ofthe active compounds as appropriate oily injection suspensions may beadministered. Suitable lipophilic solvents or vehicles include fattyoils, for example, sesame oil, or synthetic fatty acid esters, forexample, ethyl oleate or triglycerides or polyethylene glycol-400 (thecompounds are soluble in PEG-400). Aqueous injection suspensions maycontain substances which increase the viscosity of the suspensioninclude, for example, sodium carboxymethyl cellulose, sorbitol, and/ordextran. Optionally, the suspension may also contain stabilizers.

The following examples are illustrative, but not limiting, of the methodand compositions of the present invention. Other suitable modificationsand adaptations of the variety of conditions and parameters normallyencountered in clinical therapy and which are obvious to those skilledin the art are within the spirit and scope of the invention.

EXAMPLE 1 1-[4-(4-Fluorophenoxy)benzyllsemicarbazide

A mixture of 4-(4-fluorophenoxy)benzaldehyde semicarbazone (100 mg, 0.37mmol) and 5% Pd/C (45 mg) in 15 mL of MeOH was hydrogenated at 1 atm ofhydrogen overnight. The catalyst was removed by vacuum filtration overcelite and the filtrate was concentrated under reduced pressure to yielda crude product which was purified by flash chromatography using 19:1ethylacetate/MeOH with few drops of TEA per 100 mL of the solventmixture to yield 30 mg (38%) of the title compound as a white powder: ¹HNMR (DMSO-d₆) 3.74 (S, 2H), 4.97 (bs, 1H), 5.79 (bs, 2H), 6.91 (d, 2H),7.00-7.04 (m, 3H), 7.17-7.23 (m, 2H), 7.34 (d, 2H).

EXAMPLE 2 1-[4-(4-Fluorophenoxy)benzyl]-2-methylsemicarbazide

A mixture of 4-(4-fluorophenoxy)benzaldehyde-2′-methyl semicarbazone(103 mg, 0.36 mmol) and 5% Pd/C (45 mg) in 15 mL of MeOH washydrogenated at 1 atm of hydrogen overnight. The catalyst was removed byvacuum filtration over Celite and the filtrate was concentrated underreduced pressure to yield 101 mg (97%) of the title compound as a whitesolid: ¹H NMR (DMSO-d₆) 2.91 (s, 3H), 3.79 (d, 2H), 4.50 (t, 1H), 5.94(bs, 2H), 6.90 (d, 2H), 6.99-7.04 (m, 2H), 7.20 (t, 2H), 7.37 (d, 2H).

The following semicarbazides were prepared from the correspondingsemicarbazones using a similar procedure:

1-[4-(cycloheptyloxy)benzyl]semicarbazide;

1-[4-(cyclohexylmethoxy)benzyl]semicarbazide;

1-[3-fluoro-4-(4-fluorophenoxy)benzyl]semicarbazide;

1-[4-(5-indanoxy)benzyl]semicarbazide;

1-[4-(3,4-methylenedioxyphenoxy)benzyl]semicarbazide;

1-[3-(3-methylphenoxy)benzyl]semicarbazide;

1-[4-(trifluoromethyl)benzyl]-2-methylsemicarbazide;

1-[3-fluoro-4-(4-fluorophenoxy)benzyl]-2-methylsemicarbazide;

1-[4-(5,6,7,8-tetrahydro-2-naphthoxy)benzyl]semicarbazide;

1-[3-fluoro-4-(4-Fluorophenoxy)-1-phenylethyl]semicarbazide;

1-[4-(3,4-difluorophenoxy)benzyl]-2-methylsemicarbazide;

1-[4-(3,5-difluorophenoxy)benzyl]semicarbazide;

1-[4-(benzyl)benzyl]semicarbazide;

1-[4-(3,4-methylenedioxyphenoxy)benzyl]-2-methylsemicarbazide;

1-[4-(5,6,7,8-Tetrahydro-2-naphthoxy)benzyl]-2-methylsemicarbazide;

1-[3-fluoro-4-(5-Indanoxy)benzyl]semicarbazide;

1-[4-(exo-2-norbornoxy)benzyl]semicarbazide;

1-[4-(exo-2-norbornoxy)benzyl]-2-methylsemicarbazide;

1-[3-chloro-4-(4-fluorophenoxy)benzyl]semicarbazide;

1-[3-chloro-4-(4-fluorophenoxy)benzyl]-2-methylsemicarbazide;

1-[4-(phenoxy)benzyl]semicarbazide;

1-[4-(phenoxy)benzyl]-2′-methylsemicarbazide;

1-[3-[4-(2-butyl)phenoxy]benzyl]semicarbazide;

The following semicarbazides can be prepared from the correspondingsemicarbazones using a similar procedure:

1-[4-(cyclohexyloxy)benzyl]semicarbazide;

1-[3-(4-methylphenoxy)benzyl]semicarbazide;

1-[4-(3,4-difluorophenoxy)benzyl]semicarbazide;

1-[4-(2,4-difluorophenoxy)benzyl]semicarbazide;

1-[4-(2,4-difluorophenoxy)benzyl]-2-methylsemicarbazide;

1-[4-(2-fluorobenzyloxy)benzyl]semicarbazide.

EXAMPLE 3 1-[4-(4-Fluorophenoxy)benzyl]semicarbazide as Anticonvulsant

The ability of 1-[4-(4-fluorophenoxy)benzyl]semicarbazide to blockmaximal electroshock-induced seizures (MES) was determined by thefollowing procedure.

Seizures were induced by application of current (50 mA, 60 pulses/sec,0.8 msec pulse width, 1 sec duration, D.C.) using a Ugo Basile ECTdevice (model 7801). Mice were restrained by gripping the loose skin ontheir dorsal surface and saline-coated corneal electrodes were heldlightly against the two cornea. Current was applied and mice wereobserved for a period of up to 30 sec for the occurrence of a tonichindlimb extensor response. A tonic seizure was defined as a hindlimbextension in excess of 90 degrees from plane of the body.

1-[4-(4-Fluorophenoxy)benzyl]semicarbazide was administered iv to mice10 min before the test procedure. The compound exhibited protectionagainst MES with an ED₅₀ (the dose protecting 50% of animals) of 4.2mg/kg. 1-[3-Fluoro-4-(4-fluorophenoxy)benzyl]semicarbazide was tested poin mice and was found to have an ED₅₀ of 3.2 mg/kg.

EXAMPLE 4 Activity of 1-(4-(4-Fluorophenoxy)benzyl]semicarbazide asSodium Channel Blocker

1-[4-(4-Fluorophenoxy)benzyl]semicarbazide was tested in theelectro-physiological and binding assays described above and produceddose-dependent inhibition of voltage-gated sodium currents recordedHEK-293 cells stably expressing hSkM 1 sodium channels. The blockingeffect of this compound on Na⁺ currents was highly sensitive to theholding voltage, indicating that1-[4-(4-fluorophenoxy)benzyl]semicarbazide binds to voltage-sensitiveNa⁺ channels in their inactivated states and has weak potency towardsNa⁺ channels in their resting states (Ragsdale et al., Mol. Pharmacol.40:756-765 (1991); Kuo and Bean, Mol. Pharmacol. 46:716-725 (1994)). Theapparent antagonist dissociation constant (K_(d)) of this compound forinactivated sodium channels is ˜7.5 μM.

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof. All patents. patent applications and publicationscited herein are fully incorporated by reference herein in theirentirety.

1-(4-phenoxybenzyl)semicarbazide;

1-(4-(4-fluorophenoxy)benzyl)semicarbazide;

1-(4-(4-chlorophenoxy)benzyl)semicarbazide;

1-(4-(4-bromophenoxy)benzyl)semicarbazide;

1-(4-(4-methoxyphenoxy)benzyl)semicarbazide;

1-(4-(4-trifluoromethylphenoxy)benzyl)semicarbazide;

1-(4-(4-methylphenoxy)benzyl)semicarbazide;

1-(4-(3,4-difluorophenoxy)benzyl)semicarbazide;

1-(4-(4-chloro-2-fluorophenoxy)benzyl)semicarbazide;

1-(4-(4-nitrophenoxy)benzyl)semicarbazide;

1-(4-(3-methylphenoxy)benzyl)semicarbazide;

1-(4-(4-t-butylphenoxy)benzyl)semicarbazide;

1-(4-(4-propylphenoxy)benzyl)semicarbazide;

1-(4-(4-s-butylphenoxy)benzyl)semicarbazide;

1-(4-(3,4-methylenedioxyphenoxy)benzyl)semicarbazide;

1-(4-cyclohexyloxybenzyl)semicarbazide;

1-(4-cycloheptyloxybenzyl)semicarbazide;

1-[4-(5-indanyloxy)benzyl]semicarbazide;

1-(4-(6-quinolinyloxy)benzyl)semicarbazide;

1-(4-(4-fluorophenoxy)-3-fluorobenzyl)semicarbazide;

1-(4-(tetrahydropyranyloxy)benzyl)semicarbazide;

1-(4-(4-fluorophenoxy)benzyl-4-methylsemicarbazide;

1-(4-(4-fluorophenoxy)benzyl)-2-methylsemicarbazide;

1-[(4-trifluoromethyl)benzyl]-2′-methylsemicarbazide;

1-(3-(4-methylphenoxy)benzyl)semicarbazide;

1-[(4-cyclohexylmethoxy)benzyl]semicarbazide;

1-[3-fluoro-4-(4-fluorophenoxy)benzyl]semicarbazide;

1-[3-fluoro-4-(4-fluorophenoxy)benzyl]-2′-methylsemicarbazide;

1-[4-(5,6,7,8-tetrahydro-2-naphthoxy)benzyl]semicarbazide;

1-[3-fluoro-4-(4-fluorophenoxy)-1-phenylethyl]semicarbazide;

1-[4-(3,4-difluorophenoxy)benzyl]-2-methylsemicarbazide;

1-[4-(3 ,5-difluorophenoxy)benzyl]semicarbazide;

What is claimed is:
 1. A compound having the Formula I:

or a pharmaceutically acceptable salt or prodrug thereof, wherein: R₁and R₂ are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl;R₃, R₄, R₅ and R₆ are independently hydrogen, alkyl, cycloalkyl,alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkylor carboxyalkyl, or R₃ and R₄ are defined as above, and R₅ and R₆together with the nitrogen atom to which they are attached form aheterocycle A₁ and A₂ are independently aryl, heteroaryl, saturated orpartially unsaturated cycloalky or saturated or partially unsaturatedheterocycle, any of which is optionally substituted; X is one of O, S,NR₇, CH₂, C(O), NR₇C(O), C(O)NR₇, SO, SO₂ or a covalent bond; where R₇is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl,aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; n is 0, 1, 2or 3;and m is 0, 1, 2, or
 3. 2. A compound according to claim 1, wherein A₁and A₂ is phenyl optionally substituted with hydrogen, alkyl, haloalkyl,or halogen; and X is O.
 3. A compound according to claim 1, wherein A₁is phenyl optionally substituted with hydrogen, alkyl, haloalkyl, orhalogen; and A₂ is 3,4-methylenedioxyphenyl, 3,4-ethyelendioxyphenyl,indanyl or naphthyl, optionally substituted with hydrogen, alkyl,haloalkyl, or halogen.
 4. A compound of claim 1, having Formula II:

or a pharmaceutically acceptable salt or prodrug thereof, wherein: R₁,R₂, R₃, R₄, R₅, R₆, X, n and m are as defined previously in claim 1 withrespect to Formula I; and R₉, R₁₀, R₁₁ and R₁₂ independently arehydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partiallyunsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl,arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl,heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl,aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano,acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy,carbonylamino or alkylthiol; or R₉ and R₁₀ or R₁₁ and R₁₂ are takentogether with the carbon atoms to which they are attached to form acarbocycle or heterocycle. R₁₃, R₁₄, R₁₅, R₁₆ and R₁₇ independently arehydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partiallyunsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl,arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl,heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl,aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano,acylamino, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy,carbonylamino or alkylthiol; or one of R₁₃ and R₁₄, or R₁₄ and R₁₅, orR₁₅ and R₁₆, or R₁₆ and R₁₇, are taken together with the carbon atoms towhich they are attached to form a carbocycle or heterocycle.
 5. Acompound of claim 1, having Formula III or Formula IV:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:R₁-R₆, n, m, A₁, A₂ and X are as defined previously in claim 1; R₉, R₁₀,R₁₁ and R₁₂ independently are hydrogen, halo, haloalkyl, aryl,cycloalkyl, saturated or partially unsaturated heterocycle, heterocycle,heteroaryl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl,heteroarylalkyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl,hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino,ureido, cyano, acylamino, hydroxy, thiol, acyloxy, carboxy,carbonylamino or alkylthiol; or R₉ and R₁₀ or R₁₁ and R₁₂ are takentogether with the carbon atoms to which they are attached to form acarbocycleor heterocycle; R₁₃, R₁₄, R₁₅, R₁₆ and R₁₇ independently arehydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partiallyunsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl,arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl,heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl,aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro amino, ureido, cyano,acylamino, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy,carbonylamino or alkylthiol; or one of R₁₃ and R₁₄, or R₁₄ and R₁₅, orR₁₅ and R₁₆, or R₁₆ and R₁₇ are taken together with the carbon atoms towhich they are attached to form a carbocycle or heterocycle.
 6. Acompound of claim 5, wherein A₂ is an optionally substituted heteroarylor aryl group selected from the group consisting of pyridyl,pyrimidinyl, 1,3,5-triazinyl, naphthyl, quinolyl, furanyl, andthiophenyl.
 7. A compound of claim 5, wherein: A₁ is an optionallysubstituted heteroaryl or aryl group selected from the group consistingof pyridyl, pyrimidinyl, 1,3,5-triazinyl, naphthyl, quinolyl, furanyl,and thiophenyl.
 8. A compound of claim 1, having the Formula V orFormula VI:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:R₁-R₆, R₉-R₁₂, R₁₃-R₁₇, n, m and X are as defined previously withrespect to Formulae I and II; and B₁ is an optionally substituted,saturated or partially unsaturated cycloalkyl or optionally substituted,saturated or partially unsaturated heterocycle; and B₂ is an optionallysubstituted, saturated or partially unsaturated cycloalkyl or optionallysubstituted, saturated or partially unsaturated heterocycle.
 9. Acompound according to claim 8, wherein B₁ is cyclopentyl, cyclohexyl,cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl orpiperidinyl.
 10. A compound according to claim 8, wherein B₂ iscyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl,tetrahydropyranyl, pyrrolidinyl or piperidinyl.
 11. A compound accordingto claim 1, wherein said compound is 1-[4-(benzyl)benzyl]semicarbazide;1-[4-(3,4-methylenedioxyphenoxy)benzyl]-2-methylsemicarbazide;1-[4-(5,6,7,8-tetrahydro-2-naphthoxy)benzyl]-2-methylsemicarbazide;1-[3-fluoro-4-(5-Indanoxy)benzyl]semicarbazide;1-[4-(exo-2-norbornoxy)benzyl]semicarbazide;1-[4-(exo-2-norbornoxy)benzyl]-2-methylsemicarbazide;1-[3-chloro-4-(4-fluorophenoxy)benzyl]semicarbazide;1-[3-chloro-4-(4-fluorophenoxy)benzyl]-2-methylsemicarbazide;1-[4-(phenoxy)benzyl]-2-methylsemicarbazide and1-[3-[4-(2-butyl)phenoxy]benzyl]semicarbazide.
 12. A pharmaceuticalcomposition, comprising a compound of any one of claims 1-11, and apharmaceutically acceptable carrier or diluent.
 13. A method of treatinga disorder responsive to the blockade of sodium channels in a mammalsuffering therefrom, comprising administering to a mammal in need ofsuch treatment an effective amount of a compound having the Formula I:

or a pharmaceutically acceptable salt or prodrug thereof, wherein: R₁and R₂ are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl;R₃, R₄, R₅ and R₆ are independently hydrogen, alkyl, cycloalkyl,alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkylor carboxyalkyl, or R₃ and R₄ is defined as above, and R₅ and R₆together with the nitrogen atom to which they are attached form aheterocycle; A₁ and A₂ are independently aryl, heteroaryl, saturated orpartially unsaturated cycloalkyl or saturated or partially unsaturatedheterocycle, any of which is optionally substituted; X is one of O, S,NR₇, CH₂, C(O), NR₇C(O), C(O)NR₇, SO, SO₂ or a covalent bond; where R₇is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl,aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; n is 0, 1, 2 or3; and m is 0, 1, 2, or
 3. 14. The method according to claim 13, whereinA₁ and A₂ are both optionally substituted aryl moieties.
 15. The methodaccording to claim 13, wherein A₁ and A₂ are phenyl moieties which isoptionally substituted by one or two substituents independently selectedfrom the group consisting of hydrogen, C₁₋₆ alkyl, halogen, hydroxy,C₁₋₄ alkoxy or trifluoromethyl; R₁ and R₂ is hydrogen; R₃ and R₄ ishydrogen or methyl; R₅ and R₆ independently is hydrogen, C₁₋₆ alkyl, orC₃₋₇ cycloalkyl; and X is O, CH₂, or NH.
 16. The method according toclaim 13, wherein said compound is selected from the group consistingof: 1-(4-phenoxybenzyl)semicarbazide;1-(4-(4-fluorophenoxy)benzyl)semicarbazide;1-(4-(4-chlorophenoxy)benzyl)semicarbazide;1-(4-(4-bromophenoxy)benzyl)semicarbazide;1-(4-(4-methoxyphenoxy)benzyl)semicarbazide;1-(4-(4-trifluoromethylphenoxy)benzyl)semicarbazide;1-(4-(4-methylphenoxy)benzyl)semicarbazide;1-(4-(3,4-difluorophenoxy)benzyl)semicarbazide;1-(4-(4-chloro-2-fluorophenoxy)benzyl)semicarbazide;1-(4-(4-nitrophenoxy)benzyl)semicarbazide;1-(4-(3-methylphenoxy)benzyl)semicarbazide;1-(4-(4-t-butylphenoxy)benzyl)semicarbazide;1-(4-(4-propylphenoxy)benzyl)semicarbazide;1-(4-(4-s-butylphenoxy)benzyl)semicarbazide;1-(4-(3,4-methylenedioxyphenoxy)benzyl)semicarbazide;1-(4-cyclohexyloxybenzyl)semicarbazide;1-(4-cycloheptyloxybenzyl)semicarbazide;1-(4-(5-indanyloxy)benzyl)semicarbazide;1-(4-(6-quinolinyloxy)benzyl)semicarbazide;1-(4-(4-fluorophenoxy)-3-fluorobenzyl)semicarbazide;1-(4-(tetrahydropyranyloxy)benzyl)semicarbazide;1-(4-(4-fluorophenoxy)benzyl-4-methylsemicarbazide;1-(4-(4-fluorophenoxy)benzyl)-2-methylsemicarbazide;1-(3-fluoro-4-(4-fluorophenoxy)benzyl)semicarbazide;1-(3-(4-methylphenoxy)benzyl)semicarbazide;1-(4-trifluoromethyl)benzyl)-2′-methylsemicarbazide;1-[3-fluoro-4-(4-fluorophenoxy)benzyl]-2-methylsemicarbazide;1-[4-(5,6,7,8-tetrahydro-2-naphthoxy)benzyl]semicarbazide;1-[3-fluoro-4-(4-Fluorophenoxy)-1-phenylethyl]semicarbazide;1-[4-(3,4-difluorophenoxy)benzyl]-2-methylsemicarbazide; 1-[4-(3,5-difluorophenoxy)benzyl]semicarbazide;1-[4-(benzyl)benzyl]semicarbazide;1-[4-(3,4-methylenedioxyphenoxy)benzyl]-2-methylsemicarbazide;1-[4-(5,6,7,8-Tetrahydro-2-naphthoxy)benzyl]-2-methylsemicarbazide;1-[3-fluoro-4-(5-Indanoxy)benzyl]semicarbazide;1-[4-(exo-2-norbornoxy)benzyl]semicarbazide;1-[4-(exo-2-norbornoxy)benzyl]-2-methylsemicarbazide;1-[3-chloro-4-(4-fluorophenoxy)benzyl]semicarbazide;1-[3-chloro-4-(4-fluorophenoxy)benzyl]-2-methylsemicarbazide;1-[4-(phenoxy)benzyl]semicarbazide;1-[4-(phenoxy)benzyl]-2′-methylsemicarbazide and1-[3-[4-(2-butyl)phenoxy]benzyl]semicarbazide.
 17. A method fortreating, preventing or ameliorating neuronal loss following global andfocal ischemia; treating, preventing or ameliorating neurodegenerativeconditions; treating, preventing or ameliorating pain; treating,preventing or ameliorating manic depression; providing local anesthesia;or treating arrhythmias, or treating convulsions, comprisingadministering to a mammal in need of such treatment an effective amountof a compound having the Formula I:

or a pharmaceutically acceptable salt or prodrug thereof, wherein: R₁and R₂ are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl;R₃, R₄, R₅ and R₆ are independently hydrogen, alkyl, cycloalkyl,alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkylor carboxyalkyl, or R₃ and R₄ is defined as above, and R₅ and R₆together with the nitrogen atom to which they are attached form aheterocycle; A₁ and A₂ are independently aryl, heteroaryl, saturated orpartially unsaturated cycloalkyl or saturated or partially unsaturatedheterocycle, any of which is optionally substituted; X is one of O, S,NR₇, CH₂, C(O), NR₇C(O), C(O)NR₇, SO, SO₂ or a covalent bond; where R₇is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl,aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; n is 0, 1, 2 or3; and m is 0, 1, 2, or
 3. 18. The method according to claim 17, whereinmethod is for treating, preventing or ameliorating pain.
 19. The methodaccording to claim 17, wherein: A₁ and A₂ are phenyl moieties which isoptionally substituted by one or two substituents independently selectedfrom the group consisting of hydrogen, C₁₋₆ alkyl, halogen, hydroxy,C₁₋₄ alkoxy or trifluoromethyl; R₁ and R₂ is hydrogen; R₃ and R₄ ishydrogen or methyl; R₅ and R₆ independently is hydrogen, C₁₋₆ alkyl, orC₃₋₇ cycloalkyl; and X is O, CH₂, or NH.
 20. The method of claim 17,wherein: A₁ is an optionally substituted aryl group selected from thegroup consisting of phenyl and naphthyl, and A₂ is an optionallysubstituted heteroaryl or aryl group selected from the group consistingof pyridyl, pyrimidinyl, 1,3,5-triazinyl, furanyl, thiophenyl, naphthyl,quinolyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl,tetrahydronaphthyl and quinoxalinyl.
 21. The method of claim 17, whereinA₁ is an optionally substituted aryl group selected from the groupconsisting of phenyl or naphthyl, and A₂ is an optionally substitutedcycloalkyl or heterocycle selected from the group consisting ofcyclopentyl, cyclohexyl, cycloheptyl, piperidinyl, morpholinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclohexenyl,adamantyl, exo-norbornyl and cyclopentenyl.